Week 4 Flashcards
What is acromegaly caused by
Excess growth hormone
Describe the process of releasing growth hormones and its negative feedback mechanism
1) GHRH (growth hormone releasing hormone) released from the hypothalamus into anterior pituitary gland
2) This stimulates the somatotropes in anterior pituitary gland to secrete GH (growth hormone) into the blood
3) GH stimulates the release of IGF-1 from the liver
The release of IGF-1 and GH inhibits the release of GHRH and stimulates the release of somatostatin
Somatostatin is a negative regulator of GH as well
Role of somatostatin in growth hormone production
Inhibits release of growth hormone
What is IGF-1
Insulin-like growth factor released by the liver which stimulates systemic body growth and has anabolic effects
What is gigantism
Excess growth hormone during childhood causing unusually tall stature and rapid growth
Which cells secrete GH in the anterior pituitary gland
Somatotropes
Most common cause of acromegaly
Pituitary adenoma
Acromegaly can be caused by malignancy in which cells of the pituitary gland
Somatotropes
Causes of acromegaly
Pituitary adenoma
Ectopic release of GH
Ectopic release of GHRH
Hypothalamic tumours
Which cancers can cause ectopic release of GHRH
Carcinoid (neuroendocrine tumour)
Small cell lung cancer
Symptoms of acromegaly
Large hands and feet
Frontal bossing
Bulging out of lower jaw (prognathism)
Macroglossia
Obstructive sleep apnea
Enlarged nose
Visual loss
Headaches
Joint pain
What can cause visual loss
Pituitary adenomas compressing the optic chiasm
What is usually seen due to tumours compressing the optic chiasm
Bitemporal hemianopia
What is bitemporal hemianopia
partial blindness where vision is missing in the outer half of both the right and left visual field
Which conditions are at increased risk due to acromegaly
Hypertension
CVD
Colon cancer
Insulin resistance
Osteoporosis
Why may acromegaly cause obstructive sleep apnea
Due to enlarged nasopharynx; acromegaly causes thickened soft tissues
Why may hypopituitarism occur in acromegaly
Due to large pituitary adenoma causing infarction of pituitary tissue hence impairing function of the rest of the pituitary gland
What lab tests can be done to diagnose acromegaly
IGF-1 level
Oral glucose tolerance test
Why is IGF-1 level measured instead of GH
Because GH level is highly variable whereas IGF-1 is relatively constant hence more reliable
When should you do glucose tolerance test for acromegaly
If IGF-1 is raised or uncertain to confirm the diagnosis
What would the lab test results be for acromegaly (IGF-1 levels and glucose tolerance test)
Raised IGF-1 level
GH level not suppressed after administration of glucose
Why would the GH level be suppressed after administration of glucose in normal healthy people
Because GH acts like glucagon which would be suppressed due to high levels of insulin
Why may growth decrease if you eat lots of refined sugars and carbs during childhood
Because these food raises insulin level the most which would inhibit GH secretion
Except IGF-1 level and glucose tolerance test, what other tests may be done for acromegaly if patients present certain symptoms
MRI / CT / PET scan
Visual field test
Test for deficiencies in other pituitary hormones
Management of acromegaly
Surgery is first line
Drugs second
Radiotherapy third
What drugs may be used for acromegaly
Somatostatin analogues
GH antagonists (but not really used)
Examples of somatostatin analogues
Lanreotide
Octreotide
Sandostatin LAR
Effects of somatostatin analogues
Reduces GH (remember somatostatin is a negative regulator for GH)
Shrinks tumour
Relieves headache
Side effects of somatostatin analogues
Local stinging
Flatulence
Diarrhea
Abdominal pain
Gallstones
Why is GH antagonist last line for drug therapy
It doesn’t shrink tumour size
Decreases IGF-1 but serum GH concentration may increase
When is radiotherapy used to treat acromegaly
For those where surgery and drug therapy failed
Why is radiotherapy avoided in those of reproductive age
It can cause hypopituitarism and it is associated with thyroid cancer
Describe the structure of the adrenal gland
Outer layer - cortex, made of 3 layers
Center- medulla
What are the 3 layers of the cortex
Zona glomerulosa
Zona fasciculata
Zona reticularis
Function of adrenal gland
Synthesis and release of steroid hormones and catecholamines
Which steroid is synthesised and released by zone glomerulosa
Mineralcorticoids
Which layer of the adrenal cortex secretes glucocorticoids
Zona fasciculata
Which hormones are secreted by zone reticularis
Adrenal androgens
What does the medulla of adrenal gland secrete
Catecholamines
Main glucocorticoid secreted by the adrenal gland
Cortisol
Main mineralocorticoid secreted by the adrenal gland
Aldosterone
What are the catecholamines secreted by the adrenal medulla
Epinephrine (adrenaline)
Norepinephrine (noradrenaline)
Dopamine
Which cells make up the most of medulla
Chromaffin cells
What is the starting material for the synthesis of all steroids
Cholesterol
Aldosterone is regulated by which systems
Renin-angiotensin system
Cortisol and androgens are regulated by which system
Hypothalamis-pituitary- adrenal axis (HPA)
What factors can trigger the production of CRH from hypothalamus
Stress
Time of day
Illness
Describe the HPA axis
Hypothalamus secretes CRH in response to stress/illness/time of day -> CRH stimulates the release of ACTH from anterior pituitary gland -> ACTH travels through blood to the adrenal cortex to stimulate the synthesis and secretion of cortisol
Describe how dose cortisol level vary throughout the day
Highest during the day
Lowest in the night
Describe the renin-angiotensin system
1) trigger factors stimulating release of renin from kidneys
2) Renin cleaves angiotensin into angiotensin I
3) ACE cleaves angiotensin I into angiotensin II
4) Angiotensin II exerts its effects and stimulates release of aldosterone and ADH
Function of RAAS
to regulate blood pressure and fluid balance
What are the triggers for RAAS
Decrease in blood pressure (renal hypotension)
Sympathetic stimulation
Reduced sodium
Where is ACE found
Vascular endothelium of the lungs
How does angiotensin II increase blood pressure
Stimulate release of aldosterone
Stimulate release of ADH
Stimulate vasoconstriction
Increases sodium reabsorption at proximal tubule (hence water)
How does aldosterone increase blood pressure
Increases sodium retention by increasing sodium potassium channels in epithelial sodium channels in distal tubule
= increases sodium reabsorption and potassium excretion
How does ADH increase blood pressure
Insert aquaporin channels to increase permeability of the collecting duct to water
Increase sodium reabsorption at ascending limb of loop of hence (hence water)
= more water retained instead of excreted into urine
Why does high level of aldosterone lead to lower levels of potassium
Because aldosterone increases the activity of sodium potassium pump which pumps sodium in and potassium out.
How do steroids exert an action
Bind to intracellular receptors to affect transcription of certain genes
Cortisol (glucocorticoids) actions on circulation
Increase cardiac output
Increase in blood pressure
Increase in renal blood flow and filtration rate
Cortisol actions on metabolism
Increases blood sugar
Increases lipolysis
Increases proteolysis
Increases osteoclast activity
Effect on bones due to long term steroid use
Accelerated osteoporosis
Immunological effects of the cortisol
Decrease in capillary diltatation
Decrease in macrophage activity
Decrease in leukocyte migration
Dcrease in inflammatory cytokine production
Use of steroids
Suppress inflammation
Suppress immune system
Examples of when is steroid used
Asthma
RA
Ulcerative colitis, Crohn’s disease (IBD)
Effects of aldosterone through binding to mineralocorticoid receptor
Regulates blood pressure
Sodium/Potassium balance
Regulation of extracellular volume
What is Addison’s disease
= primary adrenal insufficiency (including all the primary causes)
Most common primary cause of adrenal insufficiency
Autoimmune destruction
Primary causes of adrenal insufficiency (Addison’s)
Autoimmune destruction
Surgery
Trauma
Infections
Haemorrhage (Waterhouse Friderichsen Syndrome)
Sarcoidosis / neoplasm
Which infection is associated with Addison’s
TB
Most common secondary cause of adrenal insufficiency
Chronic exogenous steroid
How may excess exogenous steroid lead to adrenal insufficiency
- steroids exert negative feedback on ACTH production hence ACTH may be suppressed for a long term -> Unable to produce enough ACTH during metabolic stress when they stop taking steroids -> adrenal insufficiency
- atrophic adrenal glands unable to respond to ACTH
Secondary causes of adrenal insufficiency
Excess exogenous steroid
Panhypopituitarism
CRH deficiency
Addison’s disease is associated with which other autoimmune diseases
T1 diabetes
Autoimmune thyroiditis (Hashimoto’s / grave’s)
Pernicious anemia
Clinical features of adrenal insufficiency
Unexplained weight loss / anorexia
Skin hyperpigmentation
Fatigue
Hypotension
Hypoglycaemia
Abdominal pain
Vomiting
Loss of pubic hair / axillary hair
Mneumonic for symptoms of adrenal insufficiency (W STEROID)
Sugar and sodium low
Tired
Electrolyte imbalance (hyperkalaemia and hyponatraemia)
Reproductive changes (loss of pubic hair / axillary hair)
O lOw blood pressure
Increased skin pigmentation
Diarrhea and vomiting
What causes skin hyperpigmentation in Addison’s disease
Due to high ACTH level stimulates melanocytes to produce melanin
Why would there be high ACTH levels in Addison’s disease
Due to low level of steroids -> less negative feedback -> ACTH and CRH not inhibited
Lab tests for adrenal insufficiency
Blood tests - Na+, K+ levels, glucose level
ACTH levels
SYNACTHEN test
Renin/aldosterone level
21 hydroxylaze autoantibodies
CT scan / MRI
What is synacthen test for adrenal insufficiency
Injection of synthetic ACTH and measure cortisol level before and 30 minutes after injection
Synacthen test that suggests adrenal insufficiency
low cortisol level 30 minutes after injection
Renin Aldosterone level that suggests adrenal insufficiency
High renin
Low aldosterone
What Na+ and K+ levels can suggest adrenal insufficiency
Hyponatraemia
Hyperkalaemia
What is the characteristic trio of lab results suggesting adrenal insufficiency
Hypoglycaemia
Hyponatraemia
Hyperkalaemia
Management of Adrenal insufficiency
Hydrocortisone
+ Fludrocortisone if aldosterone is insufficient
(usually both are used)
Sick day rules and education
Hydrocortisone is the synthetic replacement for which steroid
Cortisol
What are the sick day rules for adrenal insufficiency
Double the dose during moderate intercurrent illness
Self inject IV hydrocortisone during severe intercurrent illness
Cannot miss a dose of steroids, they need steroids for life
What is Addisonian (adrenal) crisis
Exacerbation of adrenal insufficiency where the absence of steroid hormones can lead to life-threatening situations
Symptoms of Addisonian (adrenal) crisis
Hypotension
Reduced consciousness
hypoglycaemia
Hyponatraemia
Hyperkalaemia
Very unwell
Management of Addisonian crisis
Do not delay treatment, treat ASAP
IV hydrocortisone
IV fluid resuscitation
Treat underlying cause
Monitor electrolytes, blood pressure continuously
What can trigger Addisonian crisis
Acute illness
Trauma
Infection
Withdrawal / forgot to take steroids
these causes stress which increases demand for cortisol
What happens to the adrenal gland in absence of ACTH / CRH
Atrophy due to long term failure to be exposed to and stimulated by ACTH / CRH
What are some differences in clinical features between primary and secondary adrenal insufficiencies
Primary adrenal insufficiency causes skin hyperpigmentation but secondary adrenal insufficiency will not due to no increase in ACTH
Aldosterone will not be affected because it is regulated by renin-aldosterone system instead of by ACTH / CRH
Secondary does not have hyperkalaemia
What may be excluded in the management of secondary adrenal insufficiency
The use of fludrocortisone because aldosterone is not deficient
Pathogenesis of osteoporosis
Activity of osteoclasts > activity of osteoblasts leading to decrease in bone density (bone loss)
When do people achieve their peak bone mass
Usually in their 20s
What are the regulating factors for peak bone mass
Genetics (70-80 %)
Body Weight
Sex hormones
Diet
Exercise
Is a higher peak bone mass beneficial
Yes, it is more protective against osteoporosis
Common fracture sites due to osteoporosis
Neck of femur
Humeral neck
Vertebral body
Distal radius
What can a fracture in the vertebral body lead to
Loss in height
Kyphosis due to vertebral bodies compressing into each other
What happens to the ribcage in severe kyphosis
Rests on the pelvis and causes discomfort
Risk factors of osteoporosis
Female
Age
Post-menopausal women
Oestrogen deficiency
Long term use of steroids
Alcohol, smoking
Malabsorption
Vit D / calcium deficiency
Endocrine disorders
Rheumatoid arthritis
Chronic liver disease
Why are post menopausal women at risk of osteoporosis
Due to reduced oestrogen level
Why does steroid use increases risk of osteoporosis
Increases osteoclast activity
What GI conditions can cause malabsorption hence increase risk for osteoporosis
IBD
Coeliac
What endocrine disorders increases risk of osteoporosis
Acromegaly
Hyperparathyroidism
Cushings
Diabetes
Investigations for osteoporosis
Tests to exclude non-osteoporotic low impact fractures
Fragility Fracture risk assessment ( may be skipped under certain circumstances)
DXA scan
Deficiencies in vitamin D / Calcium
Which online assessment tools are used to calculate the fragility fracture risk score
QFracture (preferred)
FRAX
When should 10-year fragility fracture risk score be calculated
Before DEXA scan except certain circumstances
Under what circumstances allow patients to be sent for DXA scan directly instead of calculating their fragility fracture risk first
> 50 female that has previous fragility fractures
<40 with major risk factors for fragility fractures
Why is QFracture preferred over FRAX
Because FRAX underestimates certain factors
What factors does FRAX underestimate
Long term use of steroids
History of multiple fragility fractures
Heavy drinking and smoking
What should be done to those with a intermediate risk of fragility fracture close to recommended threshold + with associated risk factors
Send for DXA
Even though they did not reach the threshold, it is still important to send them for DXA because they present with risk factors and also because the online assessment tools may underestimate risk of certain factors
What does T score in DXA scan represent
The number of standard deviations a patient’s bone density is from the average for a healthy young adult of the same gender
Interpret the T scores from DXA
Normal = T > -1
Osteopenia = -2.5 < T < -1
Osteoporosis = T </ -2.5
Management for those with T score > -2.5
Advise on changing habits that are risk factors for osteoporosis
Treat the conditions that are risk factors for osteoporosis
Repeat DXA within 2 years
Management for those with T score </ -2.5
Begin drug treatment
Advise on lifestyle changes
What drugs are used to treat osteoporosis
Bisphosphonates
Denosumab
Teriparatide
HRT (hormone replacement therapy)
Examples of bisphosphonates used for osteoporosis
Alendronate
Zoledronic acid
What are bisphosphonates and what are their effects
Analogues of pyrophosphate which is absorbed onto the bone and taken up by osteoclasts. This induces death of osteoclasts
Side effects of bisphosphonate
GI disturbance
Headache
Oesophagitis
Osteonecrosis (rare)
Atypical femoral fracture (rare
What can be used for a osteoporotic patient who cannot tolerate oral preparations
Yearly injection of zoledronic acid
First line drug used for osteoporosis
Bisphosphonate (aledronate)
What are the alternatives for bisphosphonate
Denosumab
Teriparatide
Romosozumab
What is denosumab and its actions
It is a mAB. It binds to RANKL to inhibit this receptor which inhibits the activity of osteoclasts
Who should be considered to be given HRT
early menopausal women
Young post-menopausal women
Side effects of HRT
Breast tenderness
Leg cramps
Changes in mood
Increases risk of blood clots, breast cancer and endometrial cancer
What lifestyle advices should be given to all patients with osteoporosis
Smoking cessation
Reduce alcohol consumption
Regular weight bearing exercises
What differentials should be taken into account when a patient presents with low impact fractures
Pathological fracture due to metastases / primary bone cancer?
Any secondary causes such as endocrine diseases / chronic liver or kidney diseases
What is Cushing’s syndrome
A condition caused by excess cortisol
Types of causes of Cushing’s syndrome
ACTH dependent
ACTH independent
Exogenous cause
ACTH dependent causes of Cushing’s syndrome
Pituitary adenoma (Cushing’s disease)
Ectopic ACTH poduction
Ectopic CRH production
What conditions can cause ectopic ACTH production
Carcinoid / carcinoma
Small cell lung cancer
Which lung cancer can cause ectopic ACTH production
Small cell lung cancer
ACTH independent causes of Cushing’s
Nodular hyperplasia
Adrenal adenoma
Adrenal carcinoma
What is the most common endogenous cause of Cushing’s
Pituitary adenoma
What is the most common cause of Cushing’s
Excess / long term use of glucocorticoids (steroids)
= iatrogenic
What conditions may require long term use of steroids
Asthma
Rheumatoid arthritis
IBD
Organ transplants
How does long term steroid use lead to adrenal cortex atrophy
Long term steroid use causes chronic suppression of ACTH. This eventually leads to atrophy of the adrenal gland due to long term failure to be exposed and respond to ACTH
Clinical features of Cushing’s
Easy bruising due to thinning of skin
Facial swelling and redness
Proximal myopathy
Buffalo hump
Increased abdominal fat
Striae
Hyperpigmentation in ACTH dependent causes of Cushing’s
Cushing’s syndrome can increase the risk of which conditions
Hypertension
Osteoporosis
Diabetes
Obesity
What is buffalo hump
collection of fat accumulated on the back of the neck
Sequence of investigations for Cushing’s
1) do tests to establish that there is excess cortisol
2) do tests to find the underlying cause
What investigations can be done to establish that there is excess cortisol
24 hour urinary free cortisol
Low dose dexamethasone suppression test
Late night salivary cortisol measurement
Describe the low dose dexamethasone suppression test
Dexamethasone is a strong glucocorticoid
Low dose dexamethasone should be able to suppress ACTH level in normal people (negative feedback). In patients with excess ACTH, low dose will not be able to suppress it.
Excess ACTH suggests excess cortisol due to ACTH dependent causes
What feature of cortisol will be absent in patients with Cushing’s syndrome when we test them with late night salivary cortisol measurement
Diurnal variation of cortisol
Investigations for identifying the cause of Cushing’s syndrome
Plasma ACTH
High dose dexamethasone suppression test
MRI/ CT / PET scan
Petrosal sinus sampling
Why is plasma ACTH level tested first in order to find the underlying cause of Cushing’s
To see whether the excess cortisol is due to ACTH independent / dependent causes
What is the high dose dexamethasone suppression test used for
To differentiate between pituitary adenoma and ectopic ACTH prodcution that is causing Cushing’s
Describe the result of high dose dexamethasone in patients with pituitary adenoma
High dose dexamethasone will be able to suppress ACTH level if the patient has pituitary adenoma. This is because the pituitary adenoma is less responsive towards normal negative feedback but it is more responsive towards high dose glucocorticoids
Describe the result of high dose dexamethasone in patients with ectopic ACTH production
ACTH level not suppressed
When is petrosal sinus sampling used for Cushings
Invasive sampling that is used if imaging / other investigations have been insufficient to reach a diagnosis
Describe the petrosal sinus sampling
Invasive procedure sampling ACTH level from the veins draining pituitary gland
If suspecting a patient with Cushing’s who is on long term steroid therapy, what investigations should you suggest
Low and high dose dexamethasone will not be useful.
Advise to lower steroid use
Management of Cushing’s syndrome
GRADUALLY stop steroids if Cushing’s was due to long term steroid use
Surgery
Drugs
Why should you gradually stop steroids instead of abruptly to treat a patient with Cushing’s
Abruptly stopping it can cause Addisonian crisis because the patients are likely to have developed suppression of their normal endogenous steroid production
= abruptly stopping it will lead to supply of steroid < demand = exacerbation of adrenal insufficiency
What drugs can be used to treat Cushing’s
Ketoconazole
Metyrapone
Mitotane
When are drugs used in the management of Cushing’s
In preparation for surgery to temporarily reduce glucocorticoid level
Long term in patients who are unfit for surgery
What is pseudo-Cushing’s
When patients present with symptoms like Cushing’s but does not have Cushing’s
What is the difference between pseudo-Cushing’s and Cushing’s
Psuedo-Cushing’s still has diurnal variation for cortisol but Cushing’s does not
What can cause pseudo-Cushing’s
Chronic alcoholism
What is primary aldosteronism
Excess of aldosterone independent of the renin-angiotensin-aldosterone system
Causes of primary aldosteronism
Bilateral idiopathic hyperplasia
Aldosterone producing adenoma (Conn’s adenoma)
Unilateral hyperplasia
Familial hyperaldosteronism
Adrenal carcinoma
What is the most common cause of primary aldosteronism
Bilateral idiopathic hyperplasia
Hallmark features of primary aldosteronism
Hypertension
Hypokalaemia
Does hypokalaemia occur in all patients with primary aldosteronism
No, only 30% of patients will have hypokalaemia.
Who should you suspect that may have primary aldosteronism
Those with moderate - severe hypertension
Those with resistant hypertension
Those with hypertension + sleep apnea
Those with hypertension + adrenal mass
Those with hypertension + family history of primary aldosteronism / family history of early onset stroke
Sequence of investigations for primary aldosteronism
1) establish that there is excess aldosterone
2) confirm diagnosis of PA
3) Find underlying cause of PA
What investigations can be done to establish that there is excess aldosterone
Measure aldosterone:renin ratio
Raised = excess aldosterone
What investigations can be done to confirm the diagnosis of primary aldosteronism
Saline suppression test
If saline does not suppress aldosterone = primary aldosteronism
What investigations can be done to find the underlying cause of primary aldosteronism
CT of adrenal gland
Adrenal vein sampling
When should adrenal vein sampling be used
To differentiate between bilateral and unilateral hyperplasia
To see whether the excess aldosterone was due to an adrenal adenoma or not
What does the management of primary aldosteronism depend on
Whether it is unilateral / bilateral
Management of primary aldosteronism (unilateral)
Unilateral adrenalectomy
Mineralocorticoid receptor antagonist
When is mineralocorticoid receptor antagonist used in the management of primary aldosteronism
Used to temporarily reduce aldosterone level to prepare patients for surgery
To be used as a long term treatment if the patient is unfit for surgery
Management of primary aldosteronism (bilateral)
Mineralocorticoid receptor antagonists
Examples of mineralocorticoid receptor antagonists
Spironolactone
Eplerenone
What is a side effect of spironolactone but not eplerenone
Gynaecomastia
What drugs can be used if mineralocorticoid receptor antagonists are not tolerated
ENaC inhibitors
What causes congenital adrenal hyperplasia (CAH)
21 hydroxylase deficiency
What is the function of 21 hydroxylase
It is an enzyme in adrenal gland required for conversion of progesterone into aldosterone and cortisol
How does 21 hydroxylase deficiency affect the steroid level
Because 21 hydroxylase is not there to convert progesterone into aldosterone and cortisol, there will be extra progesterone around.
The extra progesterone is diverted to produce more testosterone
Classic steroid levels seen in congenital adrenal hyperplasia
Low aldosterone
Low cortisol
High testosterone
Types of congenital adrenal hyperplasia
Typical: more severe form normally presented at birth / before birth
Non-typical: milder form normally presented at childhood /early adulthood
Clinical features of CAH
Adrenal insufficiency symptoms
(poor weight gain, fatigue, skin hyperpigmentation)
Adrenal crisis
Excess androgen symptoms
Genital ambiguity
Irregular periods
What are the excess androgen symptoms
Facial hair
Short
Early puberty
Deep voice
Rapid growth during childhood but final height is still shorter than average
What symptoms may not be presented in non-classic CAH
Aldosterone insufficiency (e.g. hypotension)
Investigations for CAH
Check serum concentrations of progesterone, testosterone and androgen precursors
Management for CAH
Cortisol replacement (hydrocortisone)
Aldosterone replacement in some
Surgical correction
-e.g. for those with genital ambiguity
Avoid overusing steroid treatment
What is hypercalcaemia
When the serum calcium concentration is greater than 2.6 mmol
Normal level of serum calcium
2.2 - 2.6 mol
Where can calcium be found
Mostly in bones
1% in intracellular and extracellular compartments
What is the function of calcium in intracellular compartments
For intracellular signalling
What is the function of calcium in extracellular compartments
Mostly free or bound to albumin
What is corrected level of calcium
Serum calcium level taking into account the calcium bound to albumin as well
Which factors regulate extracellular concentration of calcium
Calcitonin
PTH
Vitamin D
Which cells produce calcitonin
Parafollicular cells in thyroid gland
How is a decrease in calcium level regulated
1) Decrease in calcium level detected by CaSR in parathyroid glands
2) This stimulates the release of PTH from parathyroid glands
3) PTH stimulates
- the release of calcium from large calcium stores in bones
- increase in reabsorption of calcium in renal tubule
- activation of vitamin D
What happens when vitamin D is activated
Increases absorption of calcium in enterocytes from food
Causes of hypercalcaemia
Primary hyperparathyroidism
Tertiary hyperparathyroidism
Malignancy
Thyrotoxicity
Thiazides, lithium
Vitamin D toxicity
Familial hypocalciuric hypercalcaemia
Granulomatous diseases (TB, sarcoidosis)
What can cause vitamin D toxicity
Ingestion of excess vitamin D
Sarcoidosis
Lymphoma
What is primary hyperparathyroidism
Excessive release of PTH causing hypercalcaemia
How do malignancies cause hypercalcaemia
Some tumours can secrete PTHrP which mimics the actions of PTH
Some tumours can increase osteoclastic activity -> break down of bones -> release calcium stored
How do thiazides cause hypercalcaemia
increasing calcium reabsorption into the distal convoluted tubule in exchange for sodium.
Thiazide function: reduces sodium and water reabsorption to decrease blood pressure
What is primary hyperparathyroidism
excess production of PTH by parathyroid gland
Causes of primary hyperparathyroidism
Parathyroid hyperplasia
Parathyroid gland adenoma
Parathyroid carcinoma
What is the most common cause of primary hyperparathyroidism
Parathyroid adenoma
What is tertiary hyperparathyroidism
When the glands become autonomous after a period of prolonged secondary hyperparathyroidism, producing excessive PTH even after the cause of hypocalcaemia has been corrected
Most common cause of tertiary hyperparathyroidism
Chronic kidney disease
What is secondary hyperparathyroidism
increased secretion of PTH in response to low calcium because of kidney, liver, or bowel disease
Causes of secondary hyperparathyroidism
Vitamin D deficiency
Conditions that lead to loss of extracellular Ca2+
Calcium malabsorption / inadequate Ca2+ intake
Conditions causing abnormal PTH activity
What conditions can lead to loss of extracellular Ca2+
Pancreatitis
Rhabdomolysis
Presentation of rhabdomyolysis
Pain in proximal muscle
Myalgia
Causes of rhabdomyolysis
Severe hypothyroidism
Statins
Investigations for rhabdomyolysis
Creatinine Kinase (high)
What conditions can cause abnormal PTH activity
Kidney disease
Pseudohypoparathyroidism
What is pseudohypoparathyroidism
PTH resistance - cells unable to respond to PTH so low calcium. Low calcium triggers more PTH secretion hence high PTH
Does secondary hyperparathyroidism lead to hypercalcaemia
No, it mostly leads to low or normal calcium levels.
Effect of PTH on Ca2+ and phosphate leves
Increases calcium reabsopriton
Decreases phosphate reabsorption
Describe the lab results indicating primary hyperparathyroidism
High calcium
High / normal PTH
Decreased PO4 3-
Increased ALP
Describe the lab results indicating secondary hyperparathyroidism
Low / normal Calcium
High PTH
High PO4 3- in kidney disease
but low PO4 3- in vitamin D deficiency
Describe the lab results indicating tertiary hyperparathyroidism
High calcium
High PTH
High PO4 3- (since tertiary is usually due to chronic kidney disease)
What is familial hypocalciuric hypercalcaemia
Inherited condition causing hypercalcaemia due to mutation in CaSR
CaSR function in the kidneys
Increase excretion of Ca2+ in urine when serum Ca levels are high
Difference between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism
Hypocalciuric in FHH but not in PH
Clinical features of hypercalcaemia
Stones - renal calculi
Thrones - polyuria, constipation
Abdominal Groans- pancreatitis, abdominal pain
Moans- depression, psychosis
Bones- fragility fracture, bone pain
Hypertension
Dehydration
Thirst
How does chronic hypercalcaemia cause hypertension
Causes calcium deposits in the vessels leading to increased rate of hypertension and CVD
Investigations for hypercalcaemia
Serum Calcium
Serum PTH
LFT
Bone profile
24 hour Urinary calcium
Bone scan
X ray / US
What test results do you need confirm the diagnosis of primary hyperparathyroidism
Raised Ca
Raised PTH
Urine calcium level not elevated
What test is done to exclude familial hypocalciuric hypercalcaemia
24 hour urinary calcium - urinary calcium will be low in FHH whereas it will be normal in Primary hyperparathyroidism
Management of hypercalcaemia
IV fluids resuscitate
Bisphosphonates
Surgery
Cinacalet
Steroids
What is the treatment for granulomatous disease e.g. sarcoidosis and TB
steroids
When do patients with hypercalcaemia need to be admitted and resuscitated using IV fluids
If the patient has acute kidney injury / dehydrated
First line treatment for primary hyperparathyroidism
Surgery
What if patients with primary hyperparathyroidism doesn’t want surgery
Cinacalet first
then Bisphosphonate
Why is bisphosphonate therapy third line for hypercalcaemia caused by primary hyperparathyroidism
Because it increases bone density but it does not prevent more renal stones
PTH effect on phosphate
increase in PTH decrease phosphate
because phosphate forms insoluble salts with calcium which reduces plasma calcium level and since PTH wants to increase calcium, phosphate level needs to decrease
